DE60315391T2 - Optically active epoxy compounds and process for their preparation - Google Patents

Description

Background of the invention

Field of the invention

The The present invention relates to methods for producing optically active epoxide compounds.

Discussion of the background

The optically active epoxide compounds and optically active (2S, 3R) -2,3-Epoxypropionsäurederivate with a substituent at the 3-position of the present invention are compounds that act as intermediates for the manufacture of pharmaceuticals or agricultural chemicals.

One 3-halopropane derivative with substituents at the 1,3-positions and 2-propen-1-one with substituents at the 1,3-positions are compounds that act as intermediates for the manufacture of pharmaceuticals or agricultural chemicals.

The The present invention relates to a process for the preparation of a optically active 2,3-epoxy-3-propionic acid having a substituent the 3-position and its ester.

The optically active 2,3-epoxypropionic acid with a substituent at the 3-position and its ester of the present Invention are compounds which treatment as intermediates for the manufacture of pharmaceuticals or agricultural chemicals, as above mentioned was, are suitable.

When asymmetric epoxidation reaction is an asymmetric epoxidation reaction a trans-allyl alcohol, wherein titanium tetraisopropoxide and an optically active Diethyltartarat be used, and it will tert-butyl hydroperoxide (eg K. B. Sharpless, et al., J. Am. Chem. Soc. 109, 5765 (1987)).

Furthermore, as a method for the preparation of 2,3-epoxy-3-cyclohexylpropionic acid, a method is known, wherein cis-2,3-epoxy-4-phenylbutan-1-ol is oxidized by RuO ₄ to optically active cis-2, 3-epoxy-4-phenyl-butyric acid (eg BKB Sharpless, et al., J. Org. Chem. 50, 1560, (1985) and KB Sharpless, et al., J. Org. Chem. 1981)).

Further, as a process for producing 2,3-epoxy-4-methylpentanoic acid or 2,3-epoxyheptanoic acid, a process is known wherein the corresponding allyl alcohol is subjected to asymmetric epoxidation using titanium tetraisopropoxide and an optically active diethyl tartarate and further tert. Butyl hydroperoxide is then used, which is then oxidized into the carboxylic acid with RuO ₄ (eg. JP-A-2002-80441 ).

The conventional asymmetric epoxidation reaction was as an industrial manufacturing process not satisfactory. For example, in the conventional asymmetric epoxidation reaction of trans-allyl alcohol a size Amount of an oxidizing agent in the reaction system at the time of Reaction present, this represents a process in which a Explosion hazard, etc. was always present in the production in large quantities, although it would not have been a problem to make a small amount, but that could hardly considered as an industrial manufacturing process.

1-phenyl-3-cyclohexyl-2-propen-1-one has been described in various literatures (e.g. JP-A-11-80036 ).

It has also been known that 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one can be obtained by means of a reaction of cyclohexanecarboxyaldehyde with acetophenone (eg. International Patent Publication No. 02/041984 ).

It It was also known that a 3-hydroxy-1-carbonyl compound (an aldol), which after a known reaction of an aldehyde with a ketone is formed, readily a dehydration reaction through an acid or base experiences and an α, β-unsaturated Ketone or an α, β-unsaturated Ester forms (Herbert O. House, "Modern Synthetic Reactions Second Edition "(1972) W.A. Benjamin, Inc., pp. 632-637).

at the conventional one Processes were most likely formed by-products depending on Conditions for the resulting 1-phenyl-3-cyclohexyl-2-propen-1-one, and the desired Obtaining product in a high purity was a thorough cleaning required by, for example, silica gel column chromatography, and therefore it could hardly be considered as an industrial manufacturing process become.

When A process for producing an optically active (2S, 3R) -2,3-epoxy-3-cyclohexylpropionic acid is, for example a method known, wherein, as mentioned above, 3-cyclohexyl-2-propen-1-ol asymmetric tert-butyl hydroperoxide in the presence of an optically active Diethyltartarats and titanium tetraisopropoxide is oxidized (e.g., K. B. Sharpless, et al., J. Am. Chem. Soc. 109, 5765 (1987)) to give the optically active (2S, 3R) -2,3-epoxy-3-cyclohexylpropan-1-ol then oxidized with butenyl tetraoxide to give the desired to obtain optically active (2S, 3R) -2,3-epoxy-3-cyclohexylpropionic acid (e.g., K.B. Sharpless, et al, J. Org. Chem. 50, 1560 (1985) and K.B. Sharpless, et. al, J. Org. Chem. 46, 3936 (1981)).

Furthermore, as a method for producing an optically active α, β-epoxy carboxylate by asymmetric hydrolysis, there has been described a method wherein a lipase of α, β-epoxy carboxylate is used, wherein the substituent at the β-position is aromatic (e.g. JP-A-3-15398 ) or a linear group (eg JP-A-5-276966 ), but no application was known to an α, β-epoxy carboxylate wherein the substituent at the β-position is a cyclic alkyl group such as a cyclohexyl group.

As mentioned above was, was the conventional Process by an organic synthesis as an industrial process for the preparation of optically active (2S, 3R) -2,3-epoxypropionic acids with a substituent at the 3-position unsatisfactory.

Farther, as a process for producing an optically active α, β-epoxycarboxylate by asymmetric hydrolysis, a process has not yet been in which a lipase of an α, β-epoxy carboxylate is used wherein the substituent at the β-position is a cyclic alkyl group, like a cyclohexyl group. Furthermore, no case was known to isolate an epoxy carboxylate, the steric configuration (2S, 3R), and a (2S, 3R) -α, β-epoxycarboxylate it was necessary to isolate the (2S, 3R) -α, β-epoxycarboxylic acid, then followed by transesterification.

O. Meth-Cohn et al. have in the "Journal of the Chemical Society, Perkin Transactions 1 ", 1988, pages 2663-2674 for the preparation of Epoxidesterderivaten by epoxidation of α, β-unsaturated Esters reported with tert-butyl hydroperoxide in THF.

P. W. Baures et al. have in "Tetrahedron Letters ", 1990, Vol. 31, No. 45, pages 6501-6504 for the Baeyer-Villiger oxidation of chiral Epoxy ketones on substituted phenylglycidinestern reported.

The EP-A-1 127 885 describes the oxidation of optically active epoxyene derivatives in optically active phenylglycidinester derivatives.

Summary of the invention

Namely, the present invention provides:

A process for producing an optically active epoxy ester derivative of the above formula (3), which comprises oxidizing the optically active epoxyene derivative of the above formula (1) with an oxidizing agent,
wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group, R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group.

worin R¹ eine Methylgruppe, eine Ethylgruppe oder eine C_3-10-verzweigte, lineare oder zyklische Alkylgruppe, die in Anspruch 19 definiert ist, bedeutet.The present invention further provides:
A process for producing an optically active (2S, 3R) -2,3-epoxypropionic acid derivative having a substituent at the 3-position of the following formula (4):

wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group as defined in claim 19.

Detailed description the invention

Now become the optically active epoxide compounds of the present invention and the procedures for their Production described in detail.

In the optically active epoxyenone derivative of the above formula (1) of the present invention, the substituent R ^{1 is} a methyl group, an ethyl group or a C _3-10 linear, branched or cyclic alkyl group and may be, for example, a cyclohexyl group, an isopropyl group or an n-butyl group and the substituent R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group and may mean, for example, a phenyl group, a 4-methoxyphenyl group or a tert-butyl group.

Especially For example, the optically active epoxyenone derivative of the above formula (1) can be described in U.S. Pat For example, (2S, 3R) -2,3-epoxy-1-phenylbutan-1-one, (2S, 3R) -2,3-epoxy-1-phenylpentan-1-one, (2S, 3R) -2,3-epoxy-1-phenyl-4-methylpentan-1-one, (2S, 3R) - 2,3-epoxy-1-phenylhexane-1-one, (2S, 3R) -2,3-epoxy-1-phenylheptane-1-one, (2S, 3R) -2,3-epoxy-1-phenyloctan-1-one, (2S, 3R) -2,3-epoxy-1-phenylnonan-1-one, (2S, 3R) -2,3- epoxy-1-phenyldecane-1-one, (2S, 3R) -2,3-epoxy-1-phenylundecan-1-one, (2S, 3R) -2,3-epoxy-1-phenyldodecan-1-one, (2S, 3R) -2,3-epoxy-1-phenyl-4-dimethyl-pentan-1-one, (2S, 3R) -2,3-epoxy-1-phenyl-3-cyclohexylpropan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylbutan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylpentan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyl-4-methyl pentan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylhexan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylheptan-1-one, (2S, 3R ) -2,3-epoxy-1-tert-butyloctan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylnonan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyldecan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butylundecan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyldodecan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyl-4,4-dimethyl-pentan-1-one, (2S, 3R) -2,3-epoxy-1-tert-butyl-3-cyclohexylpropan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) butan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) pentan-1-one, (2S, 3R) -2,3-epoxy-1- (1-methoxyphenyl) -4-methyl-pentan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) -hexane-1 -one (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) heptan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) octan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) nonan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) decan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) undecan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) dodecan-1-one, (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) -4,4-dimethylpentane -1-one or (2S, 3R) -2,3-epoxy-1- (4-methoxyphenyl) -3-cyclohexylpropan-1-one be.

The optically active epoxyene derivative of the above formula (1) of the present invention can be prepared, for example, by asymmetric oxidation of the enone derivative of the formula (2):

In the enone derivative of the above formula (2) of the present invention, R ^{1 represents} a methyl group, an ethyl group or a C _3-10 linear, branched or cyclic alkyl group and may be, for example, a cyclohexyl group, an isopropyl group or an n-butyl group, and Substituent R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group and may, for example, a Phenyl group, a 4-methoxyphenyl group or a tert-butyl group.

The Manufacturing process for the enone derivative of the above formula (2) of the present invention is not subject to any particular restrictions and it can be made for example, over a crossaldol reaction of an aldehyde with acetophenone. Especially it can be prepared by reacting a silyl enol ether or a lithium enolate of acetophenone or methyl tert-butyl ketone with an aldehyde and then dehydration of the aldol derivative formed by, for example, an acid, or, in order to obtain such with a high purity, can It can be prepared by the method mentioned below on a β-haloketone with substituted 1,3-positions.

at the preparation of the epoxyenone derivative of the above formula (1) of It is preferred in the present invention to use the asymmetric oxidation reaction with cumene hydroperoxide or tert-butyl hydroperoxide by using a catalyst containing a lanthanide triisopropoxide, (R) -1,1-Bi-2-naphthol, triphenylphosphine oxide and cumene hydroperoxide includes, perform.

According to the present The invention is subject to the lanthanide triisopropoxide, which is responsible for the asymmetric oxidation reaction is not particularly limited as long as it is a rare earth metal alkoxide. However, lanthanum triisopropoxide or ytterbium triisopropoxide preferred, with particular preference lanthanum triisopropoxide.

According to the present Invention may be the lanthanide triisopropoxide, which is the asymmetric Oxidation reaction can sustain ten, be such, by a Any manufacturing process is made, and there are here no special restrictions. The lanthanide triisopropoxide is usually in an amount of 0.1 mol% to 30 mol% based on the enone derivative of the above formula (2), which is for the Reaction is used.

In of the present invention the amount of (R) -1,1'-bi-2-naphthol, the for the asymmetric oxidation reaction is used, usually 1-2 moles, preferably 1-1.5 Moles per mole of for the reaction to be used Lanthanoidisopropoxids.

In of the present invention the amount of for the asymmetric oxidation reaction to use Triphenylphosphinoxids usually from 1-5 Mol, preferably from 1.1 to 3 moles per mole of the reaction to be used Lanthanoidtriisopropoxids.

According to the present Invention is the amount of cumene hydroperoxide and tertiary butyl hydroperoxide, the for the Asymmetric oxidation reaction can be used, as a rule from 1 to 4 moles per mole of lanthanide isopropoxide at the time the formation of the catalyst, and it is still usually from 1 to 2 moles per mole of the enone derivative of the formula (1) used for the reaction is used.

In The present invention may be at the time of asymmetric Oxidation reaction the catalyst solution containing the lanthanide triisopropoxide, (R) -1,1-Bi-2-naphthol, triphenylphosphine oxide and cumene hydroperoxide includes previously prepared, and the substrate and cumene hydroperoxide or tertiary butyl hydroperoxide can previously mixed and added to the catalyst solution to the To carry out the reaction, or the substrate and cumene hydroperoxide or tertiary butyl hydroperoxide can separated into the catalyst solution be given to carry out the reaction.

In of the present invention to render the inner system anhydrous during the zeolite, like the. can keep asymmetric oxidation reaction Molecular sieves 4A or molecular sieves 3A in a powder or in molten form, in a suitable amount, as required of the case.

In In the present invention, the solvent used for the asymmetric Oxidation reaction is suitable, in particular an ether such as tetrahydrofuran (hereinafter referred to as THF), diethyl ether or diisopropyl ether or an aromatic hydrocarbon such as benzene, toluene, ethylbenzene or xylene, preferably an ether, most preferably THF.

In of the present invention, in view of the reaction temperature for the asymmetric oxidation reaction, the reaction can be carried out at a temperature be carried out from -30 ° C to 30 ° C. However, the optically active Epoxyenonderivat the above formula (1) to obtain in a high optical density, it is preferable to carry out the reaction at a temperature of -10 ° C to 20 ° C.

The Reaction time for the asymmetric oxidation reaction of the present invention varies depending on the substrate concentration, the amount of catalyst, the catalyst concentration and the reaction temperature. In general, however, the reaction will be within 0.5 to 24 hours after completion the addition of the substrate to be completed.

A Post-treatment of the asymmetric oxidation reaction of the present The invention is not subject to any particular restrictions. However, in usually a watery, saturated Ammonium chloride solution is added to decompose the catalyst, and then the in excess existing cumene peroxide is decomposed by, for example, an aqueous sodium sulfite solution, then purified with, for example, a silica gel column chromatography will be the one you want to obtain optically active Epoxyenon the above formula (1).

In the above formula (3) of the present invention, the substituent R ^{1 means} a methyl group, an ethyl group or a C _3-10 linear, branched or cyclic alkyl group which may be, for example, a cyclohexyl group, an isopropyl group or an n-butyl group, and the substituent R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group and may mean, for example, a phenyl group, a 4-methoxyphenyl group or a tert-butyl group.

Especially the optically active epoxy ester derivative of the above formula (3) For example, phenyl (2S, 3R) -2,3-epoxybutyrate, Phenyl (2S, 3R) -2,3-epoxypentanoate, phenyl (2S, 3R) -2,3-epoxy-4-methylpentanoate, Phenyl (2S, 3R) -2,3-epoxyhexanoate, phenyl (2S, 3R) -2,3-epoxyheptanoate, Phenyl (2S, 3R) -2,3-epoxyoctanoate, phenyl (2S, 3R) -2,3-epoxynonanoate, Phenyl (2S, 3R) -2,3-epoxydecanoate, phenyl (2S, 3R) -2,3-epoxyundecanoate, phenyl (2S, 3R) -2,3-epoxydodecanoate, Phenyl (2S, 3R) -2,3-epoxy-4,4-dimethyl-pentanoate, phenyl (2S, 3R) -2,3-epoxy-3-cyclohexyl-propionate, tert-Butyl (2S, 3R) -2,3-epoxybutanoat, tert -Butyl (2S, 3R) -2,3-epoxybutyl pentanoate, tert-butyl (2S, 3R) -2,3-epoxy-4-methylpentanoate, tert-butyl (2S, 3R) -2,3-epoxyhexanoate, tert-butyl (2S, 3R) -2,3-epoxyheptanoate, tert-butyl (2S, 3R) -2,3-epoxyoctanoate, tert-Butyl (2S, 3R) -2,3-epoxynonanoat, tert-butyl (2S, 3R) -2,3-epoxydecanoate, tert-butyl (2S, 3R) -2,3-epoxyundecanoate, tert-Butyl (2S, 3R) -2,3-epoxydecanoat, tert-butyl (2S, 3R) -2,3-epoxybutyl-4,4-dimethyl-pentanoate, tert-butyl (2S, 3R) -2,3-epoxy-3-cyclohexyl-propionate, 4-methoxyphenyl (2S, 3R) -2,3-epoxy-1-butanoate, 4-methoxyphenyl- (2S, 3R) -2,3-epoxypentanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxy-4-methylpentanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxyhexanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxyheptanoat, 4-methoxyphenyl- (2S, 3R) -2,3-epoxyoctanoate, 4-methoxyphenyl- (2S, 3R) -2,3-epoxynonanoate, 4-methoxyphenyl (2S, 3R) -2,3-epoxydecanoat, 4-methoxyphenyl (2S, 3R) -2,3-epoxyundecanoate, 4-Methoxyphenyl- (2S, 3R) -2,3-epoxydodecanoate, 4-methoxyphenyl- (2S, 3R) -2,3-epoxy-4,4-dimethylpentanoate or 4-methoxyphenyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate.

The Process for the preparation of the optically active Epoxidesterderivats The above formula (3) of the present invention is not subject to any special restrictions. However, it can be obtained, for example, by a reaction, wherein the optically active epoxyenone derivative of the above formula (1) is oxidized with an oxidizing agent.

The Oxidizing agent for the preparation of the optically active epoxy ester derivative of the above Formula (3) of the present invention is not subject to any special restrictions. In particular, for example, potassium persulfate, hydrogen peroxide, peracetic acid, Performic acid, trifluoroperacetic perbenzoic acid, m-chloroperbenzoic acid or mention cumene hydroperoxide. From the viewpoint of safety and handling efficiency, m-chloroperbenzoic acid is preferable.

The Oxidizing agent for the preparation of the optically active epoxy ester derivative of the above Formula (3) of the present invention is used in the Usually in an amount of 1 to 10 moles per mole of the optically active Epoxyenonderivats the above formula (1), which is used for the implementation used.

The Solvent, that for the preparation of the optically active epoxy ester derivative of the above Formula (3) of the present invention is used no special restrictions, as long as it's a solvent is that for the reaction is inert. As a rule, dichloromethane, 1,2-dichloroethane, chloroform, benzene, Toluene or ethylbenzene, for example, in an amount of 5 to 100 parts by weight, based on the epoxyenol of the above formula (1), that for the reaction is used. Furthermore, as needed pH control agents, such as sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen sulfate, Sodium dihydrogen phosphate or phosphoric acid can be further added.

The Reaction temperature and time in the preparation of the optically active Epoxyesterderivats the above formula (3) of the present invention can dependent on the kind of the epoxyenone derivative of the above formula (1) used for the reaction used, vary, and they are not subject to any special Restrictions. However, the reaction is usually within 1 to 48 hours within a temperature range of 0 to 60 ° C completed. Furthermore, can in a case where the starting material remains, the oxidizing agent continue after the reaction for added a predetermined time or the decomposition products of the oxidizing agent can be removed and then the reaction can be carried out.

A Post-treatment after the preparation of the optically active Epoxidesterderivats The above formula (3) of the present invention is not subject to any special restrictions. However, the product usually comes with an aqueous Alkali solution like a watery, saturated Natriumhydrocarbonatlösung, then washed, for example, via silica gel column chromatography is cleaned to the desired To receive product.

In The present invention is the optically active Epoxidesterderivat of the above formula (3) to give (2S, 3R) -2,3-epoxy-3-cyclohexylpropionic acid of to obtain the following formula (4). In particular, in toluene, methanol, a solvent mixture from water / methanol or a solvent mixture from water / methanol / toluene a predetermined amount of an alkaline Metal hydroxide or an alkaline alkaline earth metal hydroxide implemented.

In the above formula (4) of the present invention, the substituent R ^{1 means} a methyl group, an ethyl group or a C _3-10 linear, branched or cyclic alkyl group which may be, for example, a cyclohexyl group, an isopropyl group or an n-butyl group.

The Alkali metal hydroxide suitable for the preparation of (2S, 3R) -2,3-epoxypropionic with the substituted 3-position of the above formula (4) of the present invention Invention can be used in particular, for example Lithium hydroxide, sodium hydroxide, calcium hydroxide, rubidium hydroxide, Cesium hydroxide, magnesium hydroxide or strontium hydroxide. It is usually in a crowd from 1 to 20 mol, based on the optically active Epoxidesterderivat of the above formula (3) used in the reaction.

The Amount of solvent, that for the preparation of the (2S, 3R) -2,3-epoxypropionic acid with the substituted 3-position of the above Formula (4) of the present invention is used in the Usually 1 to 40 times, based on the weight, based on the optically active Epoxidesterderivat the above formula (3), the for the Reaction is used. Furthermore, when using a solvent mixture will be subject to the circumstances the solvent in the solvent mixture no special restrictions, and you can every relationship as long as the optically active epoxide ester derivative, that for the reaction used in solves it.

The Reaction temperature and duration for the reaction to give the (2S, 3R) -2,3-epoxypropionic acid with the substituted 3-position of the above Formula (4) of the present invention, produce, subject no special restrictions. However, the reaction usually takes about 1 to 12 hours a temperature of -5 ° C to 30 ° C to be completed.

The Post-treatment after the preparation of (2S, 3R) -2,3-epoxypropionic acid with the substituted 3-position of the above formula (4) of the present invention The invention is not subject to any particular restrictions. For example, after distilling off the solvent the oil-soluble ones Impurities are extracted and with, for example, a Ether or a halogenated hydrocarbon solvent are removed, and then an acid such as hydrochloric acid is added to the pH, to a value of at most 4, followed by an ether such as ethyl acetate or diethyl ether, is extracted and further dried and concentrated to the desired to obtain optically active (2S, 3R) -2,3-epoxy-3-propionic acid.

Now, the β-haloketone derivative of the present invention becomes a process for its production ment and a process for producing an enone derivative using the same in detail.

In the above formula (5) of the present invention, the substituent R ^{1 means} a methyl group, an ethyl group or a C _3-10 linear, branched or cyclic alkyl group which may be, for example, a cyclohexyl group, an isopropyl group or an n-butyl group, and the substituent R ² is a phenyl group, a substituted phenyl group or a tert-butyl group and may be, for example, a phenyl group, a 4-methoxyphenyl group or a tert-butyl group, and the substituent X represents a fluorine atom, a chlorine atom, a bromine atom or a Iodine atom and may preferably be a chlorine atom.

The 3-halopropan-1-one having the substituted 1,3-positions of the above formula (5) of the present invention can particularly be 3-fluoro-1-phenylbutan-1-one, 3-chloro-1-phenylbutan-1-one , 3-bromo-1-phenylbutan-1-one, 3-iodo-1-phenylbutan-1-one, 3-fluoro-1-phenyl-pentan-1-one, 3-chloro-1-phenyl-pentan-1-one, 3 -Brom-1-phenylpentan-1-one, 3-iodo-1-phenyl-pentan-1-one, 3-fluoro-1-phenyl-4-methylpentan-1-one, 3-chloro-1-phenyl-4-methylpentane 1-one, 3-bromo-1-phenyl-4-methylpentan-1-one, 3-iodo-1-phenyl-4-methylpentan-1-one, 3-fluoro-1-phenylhexan-1-one, 3 Chloro-1-phenylhexyn-1-one, 3-bromo-1-phenylhexan-1-one, 3-iodo-1-phenylhexan-1-one, 3-fluoro-1-phenylheptan-1-one, 3-chloro 1-phenylheptan-1-one, 3-bromo-1-phenylheptan-1-one, 3-iodo-1-phenylheptan-1-one, 3-fluoro-1-phenyloctan-1-one, 3-chloro-1 -phenyloctan-1-one, 3-bromo-1-phenyloctan-1-one, 3-iodo-1-phenyloctan-1-one, 3-fluoro-1-phenylnonan-1-one, 3-chloro-1-phenylnonane 1-one, 3-bromo-1-phenylnonan-1-one, 3-iodo-1-phenylnonan-1-one, 3-fluoro-1-phenyldecan-1-one, 3-chloro-1-phenyldecane-1 -one, 3-B r-1-phenyldecan-1-one, 3-iodo-1-phenyldecan-1-one, 3-fluoro-1-phenylundecan-1-one, 3-chloro-1-phenylundecan-1-one, 3-bromo- 1-phenylundecan-1-one, 3-iodo-1-phenylundecan-1-one, 3-fluoro-1-phenyldodecan-1-one, 3-chloro-1-phenyldodecan-1-one, 3-bromo-1 phenyldodecan-1-one, 3-iodo-1-phenyldodecan-1-one, 3-fluoro-1-phenyl-4,4-dimethylpentan-1-one, 3-chloro-1-phenyl-4,4-dimethylpentane 1-one, 3-bromo-1-phenyl-4,4-dimethylpentan-1-one, 3-iodo-1-phenyl-4,4-dimethylpentan-1-one, 3-fluoro-1-phenyl-3-one caclohexylpropan-1-one, 3-chloro-1-phenyl-3-caclohexylpropan-1-one, 3-bromo-1-phenyl-3-cyclohexylpropan-1-one, 3-iodo-1-phenyl-3-cyclohexylpropane 1-one, 3-fluoro-1-tert-butylbutan-1-one, 3-chloro-1-tert-butylbutan-1-one, 3-bromo-1-tert-butylbutan-1-one, 3 Iodo-1-tert-butylbutan-1-one, 3-fluoro-1-tert-butylpentan-1-one, 3-chloro-1-tert-butylpentan-1-one, 3-bromo-1 tert-butylpentan-1-one, 3-iodo-1-tert-butylpentan-1-one, 3-fluoro-1-tert-butyl-4-methylpentan-1-one, 3-chloro-1-tert .-butyl-4-methylpentan-1-one, 3-bromo-1-tert-butyl-4-methylpentane-1 -one, 3-iodo-1-tert-butyl-4-methylpentan-1-one, 3-fluoro-1-tert-butylhexan-1-one, 3-chloro-1-tert-butylhexan-1 on, 3-bromo-1-tert-butylhexan-1-one, 3-iodo-1-tert-butylhexan-1-one, 3-fluoro-1-tert-butylheptan-1-one, 3-chloro 1-tert-butylheptan-1-one, 3-bromo-1-tert-butylheptan-1-one, 3-iodo-1-tert-butylheptan-1-one, 3-fluoro-1-tert. -butyloctan-1-one, 3-chloro-1-tert-butyloctan-1-one, 3-bromo-1-tert-butyloctan-1-one, 3-iodo-1-tert-butylcotan-1 on, 3-fluoro-1-tert-butylnonan-1-one, 3-chloro-1-tert-butylnonan-1-one, 3-bromo-1-tert-butylnonan-1-one, 3-iodo 1-tert-butylnonan-1-one, 3-fluoro-1-tert-butyldecan-1-one, 3-chloro-1-tert-butyldecan-1-one, 3-bromo-1-tert. Butyldecan-1-one, 3-iodo-1-tert-butyldecan-1-one, 3-fluoro-1-tert-butylundecan-1-one, 3-chloro-1-tert-butyldecane-1 on, 3-bromo-1-tert-butylundecan-1-one, 3-iodo-1-tert-butylundecan-1-one, 3-fluoro-1-tert-butyldodecan-1-one, 3-chloro 1-tert-butyldodecan-1-one, 3-bromo-1-tert-butyldodecan-1-one, 3-iodo-1-tert-butyldodecan-1-one, 3-fluoro-1-tert. -butyl-4,4-dimethy pentan-1-one, 3-chloro-1-tert-butyl-4,4-dimethyl-pentan-1-one, 3-bromo-1-tert-butyl-4,4-dimethyl-pentan-1-one, 3 Iodo-1-tert-butyl-4,4-dimethylpentan-1-one, 3-fluoro-1-tert-butyl-3-cyclohexylpropan-1-one, 3-chloro-1-tert-butyl-3 cyclohexylpropan-1-one, 3-bromo-1-tert-butyl-3-cyclohexylpropan-1-one, 3-iodo-1-tert-butyl-3-cyclohexylpropan-1-one, 3-fluoro-1 - (4-methoxyphenyl) butan-1-one, 3-chloro-1- (4-methoxyphenyl) butan-1-one, 3-bromo-1- (4-methoxyphenyl) butan-1-one, 3-iodo 1- (4-methoxyphenyl) butan-1-one, 3-fluoro-1- (4-methoxyphenyl) -pentan-1-one, 3-chloro-1- (4-methoxyphenyl) -pentan-1-one, 3-bromo 1- (4-methoxyphenyl) pentan-1-one, 3-iodo-1- (4-methoxyphenyl) -pentan-1-one, 3-fluoro-1- (4-methoxy-phenyl) -4-methylpentan-1 on, 3-chloro-1- (4-methoxyphenyl) -4-methylpentan-1-one, 3-bromo-1- (4-methoxyphenyl) -4-methylpentan-1-one, 3-iodo-1- (4 -methoxyphenyl) -4-methylpentan-1-one, 3-fluoro-1- (4-methoxyphenyl) -hexan-1-one, 3-chloro-1- (4-methoxyphenyl) -hexan-1-one, 3-bromo- 1- (4-methoxyphenyl) hexan-1-one, 3-iodo-1- (4-methoxyphenyl) hexan-1-one, 3-Fluo r-1- (4-methoxyphenyl) heptan-1-one, 3-chloro-1- (4-methoxyphenyl) heptan-1-one, 3-bromo-1- (4-methoxyphenyl) heptan-1-one, 3 Iodo-1- (4-methoxyphenyl) heptan-1-one, 3-fluoro-1- (4-methoxyphenyl) octan-1-one, 3-chloro-1- (4-methoxyphenyl) octan-1-one, 3-bromo-1- (4-methoxyphenyl) octan-1-one, 3-iodo-1- (4-methoxyphenyl) octan-1-one, 3-fluoro-1- (4-methoxyphe nyl) nonan-1-one, 3-chloro-1- (4-methoxyphenyl) nonan-1-one, 3-bromo-1- (4-methoxyphenyl) nonan-1-one, 3-iodo-1- (4 -methoxyphenyl) nonan-1-one, 3-fluoro-1- (4-methoxyphenyl) decan-1-one, 3-chloro-1- (4-methoxyphenyl) decan-1-one, 3-bromo-1- ( 4-methoxyphenyl) decan-1-one, 3-iodo-1- (4-methoxyphenyl) decan-1-one, 3-fluoro-1- (4-methoxyphenyl) undecan-1-one, 3-chloro-1 (4-methoxyphenyl) undecan-1-one, 3-bromo-1- (4-methoxyphenyl) undecan-1-one, 3-iodo-1- (4-methoxyphenyl) undecan-1-one, 3-fluoro-1 - (4-methoxyphenyl) dodecan-1-one, 3-chloro-1- (4-methoxyphenyl) dodecan-1-one, 3-bromo-1- (4-methoxyphenyl) dodecan-1-one, 3-iodo 1- (4-methoxyphenyl) dodecan-1-one, 3-fluoro-1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one, 3-chloro-1- (4-methoxyphenyl) -4,4 -dimethylpentan-1-one, 3-bromo-1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one, 3-iodo-1- (4-methoxyphenyl) -4,4-dimethylpentan-1-one , 3-fluoro-1- (4-methoxyphenyl) -3-cyclohexylpropan-1-one, 3-chloro-1- (4-methoxyphenyl) -3-cyclohexylpropan-1-one, 3-bromo-1- (4- methoxyphenyl) -3-cyclohexylpropan-1-one or 3-iodo-1- (4-methoxyphenyl ) -3-cyclohexylpropan-1-one.

The 3-halopropan-1-one with the substituted 1,3-positions of the above For example, formula (5) of the present invention can be obtained are prepared by reacting 3-hydroxy-propan-1-one with the substituted ones 1,3-positions of the following formula (6) of the present invention, that you get after the above mentioned Process with a hydrogen halide or a hydrogen halide acid in one Solvent, that for the reaction is inert.

In the above formula (6) of the present invention, the substituent R ^{1 means} a methyl group, an ethyl group or a C _3-10 linear, branched or cyclic alkyl group which may be, for example, a cyclohexyl group, an isopropyl group or an n-butyl group, and the substituent R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group and may be, for example, a phenyl group, a 4-methoxyphenyl group or a tert-butyl group.

The 3-Hydroxypropan-1-one with the substituted 1,3-positions of the above Formula (6) of the present invention, which is for the preparation of a 3-halopropan-1-one with the substituted 1,3-positions of the above formula (5) of can be used according to a conventional Method be prepared. For example, it can easily be prepared by a method wherein an aldehyde with a Lithium enolate of acetophenone, previously prepared from acetophenone and lithium deisopropylamide at a temperature of at most -60 ° C in tetrahydrofuran (hereinafter as THF), or by a method wherein an aldehyde and a silyl enol ether of acetophenone at a temperature from -20 ° C to room temperature in a halogenated hydrocarbon solvent, such as dichloromethane, in the presence of titanium chloride (IV) are reacted. The obtained 3-Hydroxypropan-1-one with the substituted 1,3-positions can be cleaned and for the method of the present invention is used, or it can be done without cleaning for the method of the present invention can be used.

The Hydrogen halide or hydrogen halide acid, the for the Method of the present invention is particularly suitable a hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, Hydrofluoric acid, Hydrochloric acid, hydrobromic or hydriodic acid be.

In the process of the present invention, the hydrogen halide or hydrohalic acid used for the preparation of the 3-halopropan-1-one having the substituted 1,3-positions of the above formula (5) of the present invention means an aqueous one Hydrogen halide, an aqueous solution containing from 5 to 36 wt .-% of a hydrohalic acid, a mixture of a hydrogen halide and a hydrohalic acid or a solution with a hydrogen halide dissolved in an organic solvent. For example, if one wishes to prepare the 3-halopropan-1-one with the substituted 1,3-positions, aqueous hydrogen chloride, an aqueous solution containing from 5 to 36% by weight of hydrochloric acid, can be a mixture of hydrogen chloride and hydrochloric acid or a solution with hydrogen chloride dissolved in an organic solvent. Furthermore, the hydrogen halide or hydrohalic acid is usually used in an amount of 1 to 100 moles per mole of the 3-hydroxypropan-1-one with the substituted ones 1,3-positions to use for the reaction.

When Solvent, that for the preparation of the 3-halopropan-1-one with the substituted 1,3-positions of the above formula (5) of the present invention is suitable, you can use any solvent use it as long as it is opposite the reaction is inert. In particular, one can use an aromatic Hydrocarbon, such as benzene, toluene, ethylbenzene or xylene, a aliphatic hydrocarbon, such as dichloromethane, chloroform or 1,2-dichloroethane, an ether such as diethyl ether, diisopropyl ether or THF or a halogenated aromatic hydrocarbon, such as chlorobenzene or o-chlorobenzene. However, dichloromethane, Toluene or THF preferred. The solvent will be in a lot of 3- to 100 times, by weight, based on the 3-hydroxypropan-1-one with the substituted 1,3-positions used for the reaction should, used.

at the process of the present invention is the reaction temperature and duration for the preparation of the 3-halopropan-1-one with the substituted 1,3-positions of the above formula (5) usually within one Temperature range from -40 ° C to 30 ° C and within a range of 1 to 12 hours.

In The process of the present invention is used as aftertreatment after the preparation of 3-halopropan-1-one with the substituted ones 1.3 positions a big one Added amount of water, after which a liquid separation takes place and then with an aqueous sodium bicarbonate is washed and concentrated to give a crude 3-halopropan-1-one to get with the substituted 1,3-positions. The obtained crude 3-halopropan-1-one with the substituted 1,3-positions can for the next Be used without purification via the silica gel column chromatography, however, you can clean it as needed.

In of the present invention, as a process for producing the enone derivative the above formula (2) is applied to a method, wherein the 3-halopropan-1-one with the substituted 1,3-positions of the above Formula (5) as a crude product or after purification with a base in a solvent, the inert opposite the reaction is treated.

In In the process of the present invention, the base is subjected to for the Preparation of the enone derivative of the formula (2) is suitable, none special restrictions. In particular, an amine such as triethylamine, pyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo [2.2.2] octane or 1,8-diazabicyclo [5.4.0] undeca-7-ene, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or Potassium hydroxide or an alkali metal carbonate, such as lithium carbonate, Sodium carbonate or potassium carbonate, for example. she is usually in an amount of 1 to 10 moles per mole of 3-halopropan-1-one with the substituted 1,3-positions of the above formula (5), the for the Reaction is used. If furthermore an alkali metal hydroxide or an alkali metal carbonate is to be used, the solid may as it is used or it can be in the form of an aqueous solution be used. Further, when an alkali metal hydroxide or a Alkali metal carbonate is to be used, one can use a phase transfer catalyst, as a crown ether or an ammonium salt as needed.

at the process of the present invention is subject to the solvent, that for the preparation of the enone derivative of the above formula (2) is suitable is, no special restrictions, as long as it is opposite the reaction is inert. In particular, it may, for example, a aromatic hydrocarbon such as benzene, toluene, ethylbenzene or xylene, an aliphatic hydrocarbon, such as dichloromethane, Chloroform or 1,2-dichloroethane, an ether such as diethyl ether, diisopropyl ether or THF, or a halogenated hydrocarbon such as chlorobenzene or o-chlorobenzene. Of these, preferred is dichloromethane, Toluene or THF. It is usually in a lot of 3- to 100 times, by weight, based on the 3-halopropan-1-one with the substituted 1,3-positions the above formula (5), which is for the reaction used is used.

at the method according to the invention vary the reaction temperature and time to prepare the Enone derivative of the above formula (2) depending on the kind of the solvent and the kind of base that is for The reaction can be used and there are no particular restrictions. However, the reaction is usually due to a reaction within a temperature range of 10 to 70 ° C for 1 to 24 hours to be complete.

In the process of the present invention, as a post-treatment for the production of the enone derivative of the above formula (2), excess base, etc. are removed by an acid, followed by washing with water, drying and concentration, and then color components are mixed with a small amount of Kie Selsäu re removed, whereby one can obtain the desired enone derivative of the above formula (2) in high purity.

In of the present invention, it is possible by replacing the (R) -1,1'-bi-2-naphthol, as the catalyst component in the asymmetric oxidation reaction is possible with (S) -1,1'-bi-2-naphthol possible, a (2R, 3S) form, the optically symmetrical to the compound of the present invention.

According to the procedure The present invention can be a method of preparation a high purity enone derivative with substituted 1,3-positions over one new intermediate product available put. Therefore, the present invention is industrially extraordinary significant.

The inventive method is a simple and safe process using an optically active 2,3-epoxypropionic acid substituted 3-position and its ester, as intermediates for the Production of pharmaceuticals or agricultural chemicals are suitable, can be obtained in one stage, and also can the optically active 2,3-epoxy-3-cyclohexylpropionic acid in the form obtained from high purity crystals. That's why such a procedure industrially extraordinary useful.

Now become the optically active epoxide compounds of the present invention and methods for their preparation in detail with reference to the Examples are described. It should, of course, be that the present invention at all is not limited to these specific examples. The following instruments were for used the analyzes of the compounds.

¹ H NMR and ¹³ C NMR measurements:

It Gemini-200, manufactured by Varian, was used.

Infrared absorption measurement:

It was used 2000FT-IR, manufactured by Perkin Elmer.

Mass spectrometry:

It M-80B manufactured by Hitachi was used.

Specific rotation:

It SEPA-300 manufactured by Horiba Ltd. was used.

Reference Example 1

It was a 2,000 ml three-necked flask equipped with a dropping funnel and a stirrer was purged, purged with nitrogen, and then diisopropylamine (98.3 g, 971 mmol) and THF (540 mL) were added and cooled to -70 ° C. Then became n-butyllithium (15% hexane solution, 394 g, 922 mmol) dropwise over a Period of 10 minutes added, and it was for another Stirred hour at the same temperature. Then it became acetophenone (116.7 g, 971 mmol) dropwise into the same reaction solution in the given the same temperature, and it was at the same temperature for 3 hours touched, then cyclohexanecarboxyaldehyde (99.0 g, 883 mmol) was added and the reaction was for another 2 hours.

To the completion In the reaction, the reaction solution became a saturated, aqueous Ammonium chloride solution (287 g), at 0 ° C chilled and with ethyl acetate (890 ml x 2 times), after which it was concentrated to give the crude Al dolderivat to obtain. In a 200 ml three-necked flask equipped with a dropping funnel and a stirrer equipped was the obtained aldol derivative and dichloromethane (2,000 ml) given and at 0 ° C cooled, then concentrated sulfuric acid (100 g, 1.01 mol) was added, and the reaction was carried out at room temperature for 1 hour.

After completion of the reaction, washing with water (500 ml x 2 times), washing with a saturated aqueous sodium bicarbonate solution (200 ml x 4 times), liquid separation, drying, concentration and then purification were carried out by silica gel column chromatography ( Hexane / ethyl acetate from 100/0 to 90/10, v / v) to give the desired 1-phenyl-3-cyclohexyl-2-propen-1-one (156.5 g, 730 mmol) (Yield: 83%). to obtain.

Analytical results

• Melting point: 50-51 ° C
• MS (m / z) = 214 [M +]
• ¹ H-NMR (200 MHz, CDCl ₃ ) σ 1.08-1.48 (m, 5H), 1.60-1.98 (m, 5H), 2.12-2.38 (m, 1H) , 6.82 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.8, 3.3 Hz, 1H), 7.38-7.61 (m, 3H), 7.86-7.98 (m, 2H)
• ¹³ C-NMR (50 MHz, _CDCl3)
• σ 25.8, 26.0, 31.9, 41.0, 123.3, 128.3, 128.4, 132.4, 138.1, 154.7, 191.1
• IR (KBr): 2921, 2943, 1663, 1614, 1443, 1365, 1273, 1234, 1019, 985, 692 cm ^-1

example 1

One 2,000 ml three-necked flask equipped with a dropping funnel and a stirrer was flushed with nitrogen, and then dry molecular sieves 4A (200 g), (R) -1,1'-bi-2-naphthol (5.98 g, 20.9 mmol), triphenylphosphine oxide (15.84 g, 56.9 mmol) and THF (950 mL) were added and dissolved. Then it became a THF solution (40 ml) of lanthanum triisopropoxide (6.0 g, 19.0 mmol) was added, followed by then at room temperature for Stirred for 1 hour has been. Then cumene hydroperoxide (80 concentration, 6.1 g, 32.1 mmol) was added. continue to be added, and stirring was for another 2 hours at room temperature.

To confirmation, that the reaction solution became green, this was at 0 ° C cooled, and it became a THF solution (457 ml) 1-phenyl-3-cyclohexyl-2-propen-1-one (203.3 g, 949 mmol), in a separate container was placed in a dropping funnel and dropwise over a Added period of 1 hour. Then the reaction was for another 4 hours at the same temperature.

To completion the reaction became an aqueous, saturated Ammonium chloride solution Added (400 ml), and it became a 5% aqueous sodium sulfite Added (225 ml) then filtered, the liquid separated, the watery Extracted phase with dichloromethane (200 ml x 2 times), concentrated and over Silica gel column (Hexane / ethyl acetate = from 100/0 to 95/5, v / v), to the desired (2S, 3R) -1-phenyl-2,3-epoxy-3-cyclohexylpropan-1-one (174.8 g, 759 mmol) (yield: 80%).

Analytical results

• MS (m / z) = 230 [M +]
• ¹ H-NMR (200 MHz, CDCl ₃ ) σ 1.06-1.58 (m, 6H), 1.61-2.00 (m, 5H), 2.96 (dd, J = 3.3, 1.0 Hz, 1H), 4.09 (d, J = 1.0 Hz, 1H), 7.44-7.67 (m, 3H), 7.97-8.07 (m, 2H)
• ¹³ C-NMR (50 MHz, _CDCl3)
• σ 25.4, 25.6, 26.1, 29.0, 29.5, 40.1, 56.4, 64.2, 128.1, 128.7, 133.6, 135.5, 194.6
• IR (KBr): 2927, 2853, 1690, 1598, 1580, 1450, 1230, 902, 703, 666 cm ^-1
• Specific rotation [α] _D ²⁰ = -4.6 ° (C = 1.11, CHCl ₃ )
• HPLC: Chiralcel OB-H (4.6 mm ID x 250 mml), made by Daicel, hexane / isopropanol = 9/1 (vol. Ratio), 1.0 ml / min, UV = 254 nm, 6.9 min (2S, 3R), 7.7 min (2R3S), 98.0% ee.

Example 2

In a 2,000 ml eggplant type flask equipped with a Liebig reflux condenser were (2S, 3R) -1-phenyl-2,3-epoxy-3-cyclohexylpropan-1-one (40.5 g, 176 mmol) obtained in Example 1, m-chloroperbenzoic acid (70%). Purity, 130 g, 527 mmol) and toluene (850 ml), and the Reaction became at 55 ° C for 12 Hours performed.

To the completion In the reaction, the reaction solution was cooled to room temperature, and after the rainfall m-chloroperbenzoic acid (70% Purity, 87 g, 353 mmol) is further added to the reaction solution, and the reaction became 55 ° C for 12 Hours performed.

After completion of the reaction, the reaction solution was cooled to room temperature, and Excess m-chlorobenzoic acid was decomposed with a 5% aqueous sodium sulfite solution (500 g), the precipitates were filtered off, followed by washing with an aqueous saturated sodium bicarbonate solution (200 ml x 6 times) and purified by silica gel column chromatography (hexane / ethyl acetate = of 100/0 to 95/5, v / v) to give the desired phenyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate (34.7 g, 141 mmol) (yield: 80%). ) to obtain.

Analytical results

• Melting point: 59-60 ° C
• MS (m / z) = 246 [M +]
• ¹ H-NMR (200 MHz, CDCl ₃ ) σ 1.05-1.52 (m, 6H), 1.61-1.97 (m, 5H), 3.15 (dd, J = 3.2, 1.0 Hz, 1H), 3.50 (d, J = 1.0 Hz, 1H), 7.08-7.45 (m, 5H)
• ¹³ C-NMR (50 MHz, CDCl ₃₎ σ 25.4, 25.6, 26.2, 28.8, 29.3, 39.5, 51.9, 63.0, 121.1, 126, 1, 129.4, 150.1, 168.0
• IR (KBr): 2931, 2848, 1769, 1483, 1449, 1242, 1184, 1172, 1156, 972, 881, 777, 722, 690 cm ^-1
• Specific rotation [α] _D ²⁰ = + 13.5 ° (C = 1.08, CHCl ₃ )
• HPLC: Chiralcel OB-H (4.6 mm ID x 250 mml), made by Daicel, hexane / isopropanol = 9/1 (vol. Ratio), 1.0 ml / min, UV = 254 nm, 5.6 min (2S, 3R), 7.3 min (2R, 3S),> 99.0% ee.

Example 3

In a 2,000 ml three-necked flask equipped with a dropping funnel and a stirrer phenyl (2S, 3R) -2,3-epoxy-3-cyclohexylpropionate (54.0 g, 219 mmol) obtained in Example 2 and methanol (437 ml), and to 0 ° C cooled. Then a 4% aqueous sodium hydroxide (250 g, 250 mmol) given a period of 1 hour, and the reaction was for further 2 hours at the same temperature. After completion sodium dihydrogen phosphate dihydrate (3.42 g) was added to the reaction, and then the solvent became distilled off. Then water (250 ml) was added followed by with dichloromethane (50 ml x 4 times) was extracted. Then sodium dihydrogen phosphate dihydrate became (116g) added, followed by ethyl acetate (50 ml × 4 times) was extracted. Then, a 10% aqueous hydrochloric acid (200 ml), and the pH was adjusted to 3, followed by ethyl acetate (50 ml × 3 times) was extracted, dried and concentrated to give the crude (2S, 3R) -2,3-epoxy-3-cyclohexylpropionic acid (20.5 g). The obtained crude product was n-heptane / toluene = 2/1 (V / v) to give the desired (2S, 3R) -2,3-epoxy-3-cyclohexylpropionic acid (18.0 g, 106 mmol) (yield: 48%).

Analytical results

• Melting point: 64-65 ° C
• MS (m / z) = 170 [M +]
• ¹ H-NMR (200 MHz, CDCl ₃ ) σ 0.98-1.48 (m, 6H), 1.56-1.94 (m, 5H), 3.03 (dd, J = 3.1, 1.0 Hz, 1H), 3.32 (d, J = 1.0 Hz, 1H), 10.85-11.23 (br, 1H)
• ¹³ C-NMR (50 MHz, CDCl ₃₎ σ 25.4, 25.5, 26.0, 28.7, 29.2, 39.4, 51.4, 63.1, 175.2
• IR (KBr): 3009, 2929, 2851, 1715, 1638, 1448, 1252, 902, 882, 678 cm ^-1
• Specific rotation [α] _D ²⁰ = + 20.8 ° (C = 1.04, CHCl ₃ )
• HPLC: Chiralcel OD-H (4.6 mm ID x 250 mml), made by Daicel, hexane / isopropanol / trifluoroacetic acid = 95/5 / 0.5 (v / v), 1.0 ml / min
• UV = 210 nm, 6.5 min (2S, 3R), 7.2 min (2R, 3S),> 99.0% ee.

Example 4

There was obtained (2S, 3R) -2,3-epoxy-1-phenyl-4-methylpentan-1-one in a yield of 92% with an optical purity of 96% in the same manner as in Example 1, except for in that 1-phenyl-3-cyclohexyl-2-propan-1-one was changed to 1-phenyl-4-methyl-2-penten-1-one.
¹ H-NMR (200 MHz, _CDCl3) δ 1.07 (d, J = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 1.62 to 1, 84 (m, 1H), 2.97 (dd, J = 6.6, 1.8Hz, 1H), 4.07 (d, J = 1.8Hz, 1H), 7.48-7.66 (m, 3H), 8.02-8.08 (m, 2H)
¹³ C-NMR (50 MHz, _CDCl3)
δ 18.4, 19.0, 30.7, 56.6, 65.1, 128.2, 128.8, 133.7, 194.6
MASS (m / z) = 190 [M +]
IR (KBr): 3062, 2965, 2872, 1692, 1598, 1470, 1450, 1367, 1285, 1230, 1180, 1075, 943, 891, 831, 697, 665 cm ^-1
Specific rotation [α] _D ²⁰ = -24 ° (C = 1.00, CHCl ₃ )

Elemental analysis

• Calculated values C ₁₂ H ₁₄ O ₂ : C, 75.76; H, 7,42
• Measured values: C, 75.68; H, 7,39

Example 5

There was obtained phenyl (2S, 3R) -2,3-epoxy-4-methylpentanoate in 68% yield in the same manner as in Example 2 except that (2S, 3R) -2 obtained in Example 4 was obtained , 3-epoxy-1-phenyl-4-methylpentan-1-one was used.
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.62-1, 84 (m, 1H), 3.14 (dd, J = 6.2, 1.8 Hz, 1H), 4.48 (d, J = 1.8 Hz, 1H), 7.10-7.34 (m, 5H)
¹³ C-NMR (50 MHz, CDCl ₃₎ δ 18.3, 18.8, 30.1, 52.0, 63.9, 121.2, 125.3, 126.2, 128.2, 129, 0, 129.5, 167.9
MASS (m / z) = 206 [M +]
IR (KBr): 2967, 2876, 1774, 1754, 1593, 1493, 1451, 1353, 1266, 1194, 1169, 969, 895, 713, 688 cm ^-1
Specific rotation [α] _D ²⁰ = -6.2 ° (C = 1.00, CHCl ₃ )

Elemental analysis

• Calculated values C ₁₂ H ₁₄ O ₃ : C, 69.88; H, 6,84
• Measured values C, 70.01; H, 6,66

Example 6

There was obtained (2S, 3R) -2,3-epoxy-4-methylpentanoic acid in a yield of 85% in the same manner as in Example 3 except that the phenyl (2S, 3R) -2 obtained in Example 5 was obtained , 3-epoxy-4-methylpentanoate was used.
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.00 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 1.59-1, 78 (m, 1H), 3.03 (dd, J = 5.6, 1.8 Hz, 1H), 3.31 (d, J = 1.8 Hz, 1H), 11.1 (bs, 1H )
¹³ C-NMR (50 MHz, CDCl ₃₎ δ 18.1, 18.7, 30.1, 51.6, 64.0, 175.2
MASS (m / z) = 152 [M +]
IR (KBr): 3050, 2968, 1725, 1452, 1369, 1284, 1220, 895, 821, 666 cm ^-1
Specific rotation [α] _D ²⁰ = + 2.7 ° (C = 1.00, CHCl ₃ )

Elemental analysis

• Calculated values C ₆ H ₁₀ O ₃ : C, 55.37; H, 7,14
• Measured values: C, 55.22; H, 7.58

Example 7

(2S, 3R) -2,3-epoxy-1-phenylheptan-1-one was obtained in 89% yield with an optical density of 92% in the same manner as in Example 1, except that 1- Phenyl-3-cyclohexyl-2-propen-1-one was changed to 1-phenyl-2-hepten-1-one.
¹ H-NMR (200 MHz, _CDCl3) δ 0.94 (r, J = 7.0 Hz, 3H), 1.40 to 1.84 (m, 6H), 3.14 (dt, J = 5 , 8, 1.8 Hz, 1H), 4.02 (d, J = 1.8 Hz, 1H), 7.48-7.66 (m, 3H), 8.02-8.08 (m, 2H)
¹³ C-NMR (50 MHz, CDCl ₃₎ δ 14.0, 22.5, 28.0, 31.7, 57.5, 60.1, 128.2, 128.5, 128.8, 133, 7, 194.6
MASS (m / z) = 204 [M +]
IR (KBr): 2959, 2993, 2872, 1690, 1598, 1450, 1426, 1231, 1002, 937, 906, 765, 735, 699 cm ^-1
Specific rotation [α] _D ²⁰ = + 7.3 ° (C = 1.00, CHCl ₃ )

Elemental analysis

• Calculated values C ₁₃ H ₁₆ O ₂ : C, 76.44; H, 7,90
• Measured values: C, 76.68; H, 7.99

Example 8

Phenyl (2S, 3R) -2,3-epoxyheptanoate was obtained in 65% yield in the same manner as in Example 2 except that the (2S, 3R) -2,3-epoxy obtained in Example 7 was obtained 1-phenylheptan-1-one ver was turned.
¹ H-NMR (200 MHz, _CDCl3) δ 0.94 (t, J = 7.2 Hz, 3H), 1.33 to 1.82 (m, 1H), 3.33 (dt, J = 6 , 2, 1.8 Hz, 1H), 3.44 (d, J = 1.8 Hz, 1H), 7.06-7.48 (m, 5H)
¹³ C-NMR (50 MHz, CDCl ₃₎ δ 14.0, 22.5, 27.9, 31.2, 53.0, 59.0, 121.2, 125.3, 126.2, 128, 2, 128.4, 129.0, 129.5, 129.8, 167.8
MASS (m / z) = 220 [M +]
IR (KBr): 2958, 2933, 2873, 1773, 1753, 1593, 1493, 1455, 1344, 1266, 1194, 1169, 1108, 1070, 1026, 956, 688 cm ^-1
Specific rotation [α] _D ²⁰ = + 15.4 ° (C = 1.00, CHCl ₃ )

Elemental analysis

• Calculated values C ₁₃ H ₁₆ O ₃ : C, 70.89; H, 7,32
• Measured values: C, 70.76; H, 7.56

Example 9

72% of (2S, 3R) -2,3-epoxyheptanoic acid was obtained in the same manner as in Example 3, except that the phenyl (2S, 3R) -2,3-epoxyheptanoate obtained in Example 8 was obtained has been used.
¹ H-NMR (200 MHz, _CDCl3) δ 0.92 (t, J = 7.0 Hz, 3H), 1.26 to 1.72 (m, 6H), 3.19 (m, 1H), 3.25 (bs, 1H), 9.66 (bs, 1H)
¹³ C-NMR (50 MHz, CDCl ₃₎ δ 13.9, 22.4, 27.8, 31.2, 52.8, 59.0, 174.6
MASS (m / z) = 144 [M +]
IR (KBr): 3070, 2959, 2935, 2874, 1736, 1460, 1378, 1243, 1046, 901, 667 cm ^-1
Specific rotation [α] _D ²⁰ = + 20.4 ° (C = 1.00, CHCl ₃ )

Elemental analysis

• Calculated values: C ₇ H ₁₂ O ₃ : C, 58.32; H, 8,39
• Measured values: C, 58.12; H, 8,21

Now become the β-haloketone derivative of the present invention, a process for its preparation and the method for producing an enone derivative using the same in detail with reference to the examples. However, of course, should be that the present invention in no way to these specific Examples limited is. The following tools were used for the analysis of the compounds used.

¹ H-NMR and ¹³ C-NMR measurements:

 It Gemini-2000 manufactured by Varian was used.

Purity measurement by HPLC:

Measured with CCPM, manufactured by TOSOH CORPORATION, TSKgel80TQA (1.6 mm ID × 150 mml), manufactured by TOSOH CORPORATION, UV-8020 detector (UV = 254 nm), manufactured by TOSOH CORPORATION, eluent: acetonitrile / water = 9/1 (v / v), 1 ml / min.

Production Example 1

One 2,000 ml three-necked flask equipped with a dropping funnel and a stirrer, was purged with nitrogen, and then diisopropylamine (98.3 g, 971 mmol) and THF (540 ml) and cooled to -70 ° C. Then became n-butyllithium (15 hexane solution, 394 g, 922 mmol) a. Period of 10 minutes added drop by drop, after which then for for an additional 1 hour at the same temperature was stirred. Then acetophenone (116.7 g, 971 mmol) was added dropwise to the same reaction solution added at the same temperature, then for 3 hours stirred at the same temperature and then Cyclohexanecarboxyaldehyde (99.0 g, 883 mmol) was added and the reaction for another 2 hours has been.

After completion of the reaction, the reaction solution was poured into a saturated aqueous Am ammonium chloride solution (287 g) cooled to 0 ° C, then extracted with ethyl acetate (890 ml x 2 times) and concentrated to give crude 1-phenyl-3-hydroxy-3-cyclohexylpropan-1. on (194.8 g, 855 mmol).

Example 10

In a 2,000 ml three-necked flask equipped with a dropping funnel and a stirrer was equipped, were obtained in Preparation Example 1 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one (93.5 g, 402 mmol) and dichloromethane (850 g) and cooled to -10 ° C. Then was 36% hydrochloric acid (180 g, 1.78 mol) dropwise over a period of 30 minutes was added and the reaction became at the same temperature for another 2 hours.

After completion of the reaction, water (700 ml) was added and stirred, after which the liquid was separated, washed with saturated aqueous sodium bicarbonate solution (250 ml x 3 times) and then concentrated, whereby 1-phenyl-3-chloro 3-cyclohexylpropan-1-one (95.9 g, 382 mmol) in a yield of 95.
¹ H-NMR (200 MHz, CDCl ₃ ) σ: 1.08-1.51 (5H, m), 1.58-1.95 (6H, m), 3.23 (1H, dd, J = 4 , 4 Hz, 16.8 Hz), 3.56 (1H, dd, J = 8.8 Hz, 16.8 Hz), 4.52 (1H, ddd, J = 4.4 Hz, 4.4 Hz , 8.8 Hz), 7.42-7.65 (3H, m), 7.96 (2H, d, J = 7.0 Hz).

Example 11

The Reaction and aftertreatment were done in the same way as in Example 10 performed, with the exception that 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one, the one according to the same manufacturing method as in the production example 1, was used as starting material, and it became the 36% Hydrochloric acid (180 g) in 15% hydrochloric acid (250 ml), whereby in a yield of 91%, the desired 1-phenyl-3-chloro-3-cyclohexylpropan-1-one (92.0 g, 366 mmol) received.

Example 12

The Reaction and aftertreatment were carried out in the same way as in Example 10 performed, with the exception that 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one, the one according to the same manufacturing method as in the production example 1, used as starting material, and the hydrochloric acid (180 g) was changed to hydrogen chloride gas (20 ° C, 12,300 ml, 511 mmol), and the reaction was carried out at -20 ° C, whereby in a yield of 96%, the desired 1-phenyl-3-chloro-3-cyclohexylpropan-1-one (97.1 g, 407 mmol).

Example 13

In a 1,000 ml three-necked flask equipped with a dropping funnel and a stirrer was equipped, the 1-phenyl-3-chloro-3-cyclohexylpropan-1-one obtained in Example 10 were (50 g, 199 mmol) and the dichloromethane (300 g) and cooled to 0 ° C. Then was triethylamine (30 g, 296 mmol) over a period of 1 hour added dropwise, after which it was then heated at 45 ° C, and the reaction was carried out at the same temperature for 4 hours.

To the completion In the reaction, the reaction solution was cooled to room temperature, followed by then washed with water (150 ml), with 1N hydrochloric acid (150 ml × 2 times), with an aqueous, saturated sodium (240 ml × 2 ml), dried and concentrated to give the crude 1-Phenyl-3-cyclohexyl-2-propen-one received. Furthermore, the purification was done over a short column, the Was packed with silica gel (50 g), which is the desired 1-phenyl-3-cyclohexyl-2-propen-1-one (40.6 g, 180 mmol) (yield: 95%). Furthermore, that was Result of the purity measurement with HPLC 97%.

Example 14

The Reaction and post-treatment were carried out in the same manner as in Example 13 performed, with the exception that 1-phenyl-3-cyclohexyl-2-propen-1-one, the one according to the same manufacturing method as in Example 10 was used, the triethylamine (30 g, 296 mmol) in 4-dimethylaminopyridine (26.9 g, 220 mmol) was changed and the reaction temperature was at 20 ° C changed has been.

The 1-phenyl-3-cyclohexyl-2-propen-1-one obtained (41.5 g, 193 mmol) was in a yield of 97% and had an HPLC purity of 98%.

Example 15

The Reaction and aftertreatment were done in the same way as in Example 13 was carried out with the exception of that according to the same manufacturing process 1-phenyl-3-cyclohexyl-2-propen-1-one obtained as in Example 11 The triethylamine (30 g, 296 mmol) in sodium carbonate was used (53.0 g, 500 mmol) changed and the 18-crown-6-ether (2 g) and the reaction temperature in 50 ° C changed has been.

The 1-phenyl-3-cyclohexyl-2-propen-1-one obtained (39.7 g, 185 mmol) was in 93% yield and had a PHLC purity of 94% on.

Example 16

1-Phenyl-4-methyl-3-chloropentan-1-one was obtained in 92% yield by reacting in the same manner as in Example 10 using 1-phenyl-1-methyl-3-hydroxypentane. 1-one, which was prepared from 2-methylpropanal and acetophenone according to Preparation Example 1, was carried out.
¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.05 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 2.09 (m, 1H), 3.21 (dd, J = 16.0, 4.2 Hz, 1H), 3.59 (dd, J = 16.0, 8.0 Hz, 1H), 4.58 (m, 1H ), 7.46-7.66 (m, 3H), 7.92-8.04 (m, 2H).
MASS (m / z) = 210 [M +]

Elemental analysis

• Calculated values: C ₁₂ H ₁₅ ClO: C, 68.40; H, 7,18
• Measured values: C, 68.43; H, 7,17

Example 17

There was obtained 1-phenyl-4-methyl-2-penten-1-one in a yield of 89% with a purity of 96% by reacting in the same manner as in Example 13 using 1-phenyl-4-one. methyl-3-hydroxypentan-1-one obtained in Example 16.
¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.13 (d, J = 6.8 Hz, 6H, 2.48-2.66 (m, 1H, 6.82 (d, J = 7.9 Hz, 1H), 7.04 (dd, J = 15.8, 6.6 Hz, 1H), 7.42-7.59 (m, 3H), 7.90-7.99 (m, 2H) ,
¹³ C-NMR _(CDCl3) δ 21.5, 31.6, 123.1, 128.2, 128.4, 128.5, 132.5, 138.1, 155.9, 191.2
MASS (m / z) = 174 [M +]
IR (KBr) 3060, 2963, 2870, 1670, 1621, 1465, 1447, 1354, 1304, 1270, 1217, 1018, 983, 960, 772, 607, 660 cm ^-1

Elemental analysis

• Calculated values: C ₁₂ H ₁₄ O: C, 82.72; H, 8,10
• Measured values: C, 82.78; H, 8,20

Example 18

1-Phenyl-3-chloroheptan-1-one was obtained in a yield of 92% by reacting in the same manner as in Example 10 using 1-phenyl-3-hydroxyheptan-1-one obtained from n- Pentanal and acetophenone was prepared according to Preparation Example 1 was carried out.
¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.93 (t, J = 6.8 Hz, 3H), 1.30-1.95 (m, 6H), 3.27 (dd, J = 18 , 0, 3.2 Hz, 1H), 3.59 (dd, J = 18.0, 3.2 Hz, 1H), 4.58 (m, 1H), 7.44-7.64 (m, 3H), 7.95-8.06 (m, 2H)
MASS (m / z) = 224 [M +]

Elemental analysis

• Calculated values: C ₁₃ H ₁₇ ClO: C, 69.48; H, 7,62
• Measured values: C, 69.45; H, 7,60

Example 19

1-Phenyl-2-hepten-1-one was obtained in a yield of 85% with a purity of 98% by reacting in the same manner as in Example 13 using the 1-phenyl-4-one obtained in Example 18. methyl-3-chloroheptan-1-one was carried out. ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.93 (t, J = 6.8 Hz, 3H), 1.32-1.57 (m, 4H), 2.26 (m, 2H), 6.70 (d, J = 14.0 Hz, 1H), 7.04 (dt, J = 14.0, 6.6 Hz, 1H), 7.42-7.59 (m, 3H), 7 , 88-7,99 (m, 2H)
¹³ C-NMR _(CDCl3) δ 13.9, 22.4, 30.4, 32.6, 125.8, 128.4, 128.5, 138.0, 150.0, 190.8
MASS (m / z) = 188 [M +]
IR (KBr) 3060, 2958, 2930, 2872, 1671, 1621, 1448, 1358, 1282, 1265, 1223, 1004, 983, 924, 760, 693 cm ^-1

Elemental analysis

• Calculated values: C ₁₃ H ₁₆ O: C, 82.94; H, 8,57
• Measured values: C, 82.78; H, 8,40

Comparative Example 1

Under Use of the 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one obtained in Example 10 (50 g, 215 mmol), with the 36% hydrochloric acid concentrated in sulfuric acid (100 g, 1.01 mol) changed was, the reaction was at 0 ° C for 2 hours carried out.

To completion the reaction, was washed with water (500 ml x 2 times), washing with saturated, aqueous sodium (200 ml × 4 times), the liquid separation, drying and concentration to give crude 1-phenyl-3-cyclohexyl-2-propan-1-one to obtain.

The Purification of the obtained crude 1-phenyl-3-cyclohexyl-2-propan-1-one was carried over the Silica gel column with a silica gel (50 g), which gives the desired 1-phenyl-3-cyclohexyl-2-propan-1-one (36.3 g, 169 mmol), but the purity was HPLC measurement low with a value of 83%.

The entire revelations of Japanese Patent Application No. 2002-279147 , filed on 25 September 2002, Japanese Patent Application No. 2002-279148 , filed on September 25, 2002 and Japanese Patent Application No. 2002-311302 , filed on October 25, 2002, including the specifications, claims and abstracts are incorporated herein in their entirety.

worin R¹ eine Methylgruppe, eine Ethylgruppe oder eine C_3-10-verzweigte, lineare oder cyclische Alkylgruppe bedeutet und R² eine Phenylgruppe, eine substituierte Phenylgruppe oder eine tert.-Butylgruppe bedeutet.An optically active epoxyenone derivative of the following formula (1):

wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group and R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group.

Claims (20)

Process for the preparation of an optically active epoxy ester derivative of the formula (3),

the oxidation of the optically active epoxyenone derivative of the formula (1),

wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group and R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group, with an oxidizing agent. A process according to claim 1, wherein in the formula (1), R ^{1 represents} a cyclohexyl group, an isopropyl group or an n-butyl group. A process according to claim 1 or 2, wherein in the formula (1), R ^{2 represents} a phenyl group, a 4-methoxyphenyl group or a tert-butyl group. A process according to claim 1, wherein the epoxyenone derivative of the formula (1) is obtained by asymmetric oxidation of an enone derivative of the following formula (2):

wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group and R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group. A process according to claim 4, wherein in the formula (2), R ^{1 represents} a cyclohexyl group, an isopropyl group or an n-butyl group. A process according to claim 4 or 5, wherein in the formula (2), R ^{2 represents} a phenyl group, a 4-methoxyphenyl group or a tert-butyl group. A process according to any one of claims 4 to 6, wherein the enone derivative of the formula (2) asymmetrically by cumene hydroperoxide or tert-butyl hydroperoxide in the presence of a catalyst containing a lanthanide triisopropoxide, (R) -1,1'-bi-2-naphthol and Triphenylphosphine oxide is oxidized. The method of claim 7, wherein the lathanoid triisopropoxide Lanthanum triisopropoxide is. A process according to claim 4 wherein the α, β-unsaturated ketone derivative of formula (2) is prepared by treating a 3-halopropan-1-one derivative having substituents at the 1,3-positions of formula (5),

wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group, R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group, and X represents a fluorine atom, a chlorine atom, a bromine atom or Iodine atom is obtained with a base. A process according to claim 9, wherein in the formula (5), R ^{1 represents} a cyclohexyl group, an isopropyl group or an n-butyl group. A process according to claim 9 or 10, wherein in the formula (5), R ^{2 represents} a phenyl group, a 4-methoxyphene nyl group or a tert-butyl group. A method according to any one of claims 9 to 11, wherein in the Formula (5) X represents a chlorine atom. A process according to claim 9, wherein the 3-halopropan-1-one derivative is obtained by reacting a β-hydroxyketone derivative represented by the following formula (6):

wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group and R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group, with a hydrogen halide or a halohalide acid. A process according to claim 13, wherein in the formula (6), R ^{1 represents} a cyclohexyl group, an isopropyl group or an n-butyl group. A process according to claim 13 or 14, wherein in the formula (6), R ^{2 represents} a phenyl group, a 4-methoxyphenyl group or a tert-butyl group. The method of claim 13, wherein 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one with hydrogen chloride or hydrochloric acid to give phenyl-3-chloro-3-cyclohexylpropan-1-one manufacture. The method of claim 13, wherein 1-phenyl-3-hydroxy-4-methylpentan-1-one with hydrogen chloride or hydrochloric acid to give phenyl-3-chloro-4-methylpentan-1-one manufacture. The method of claim 13, wherein 1-phenyl-3-hydroxyheptan-1-one with hydrogen chloride or hydrochloric acid to give phenyl-3-chloroheptan-1-one manufacture. A process for producing an optically active (2S, 3R) -2,3-epoxypropionic acid derivative having a substituent at the 3-position of the following formula (4):

wherein R ^{1 represents} a methyl group, an ethyl group or a C _3-10 branched, linear or cyclic alkyl group, which comprises the oxidation of the optically active epoxyenone derivative of the formula (1),

wherein R ^{1 is} as defined above and R ^{2 represents} a phenyl group, a substituted phenyl group or a tert-butyl group, with an oxidizing agent, and further hydrolyzing the optically active oxide ester derivative of the formula (3) thus obtained:

wherein R ¹ and R ^{2 are} as defined above. A process according to claim 19, wherein in the formula (4), R ^{1 represents} a cyclohexyl group, an isopropyl group or an n-butyl group.